stereo selectivity

Pharmacology & Toxicology 1989, 65, 321-331. MiniReview

The Stereoselectivity of Drug Action Donald F. Smith

Psychopharmacology Research Unit, Psychiatric Hospital, Skovagervej 2, DK-8240 Risskov, Denmark (Received December 16, 1988; Accepted June 6, 1989)

For Index to compounds and structural drawings, see page 328 and 329.

Pharmacologists and toxicologists are in the midst of dem- onstrating the importance of spatial (three-dimensional) molecular features in the functions of biological systems and in the therapeutic actions and side effects of drugs. Recent findings indicate that spatial features in a variety of biologically active molecules play a decisive role in many life processes and in effects of drugs on those processes (Smith 1989a). The dependence of drug-receptor interactions on spatial features in their components is known as stereoselectivity (Portoghese 1970). The purpose of this Mi- niReview is to present the results of some studies on the stereoselectivity of drug action and toxicity, and to discuss their implications.

History in brief: Louis Pasteur was among the first to recognize the importance of spatial features in organic products, although herbal remedies containing stereoisomers had been used as drugs for centuries (Riddle 1974). In 1860, Pasteur postulated that most essential products of life are asymmetric (Robinson 1974). In 1897, Paul Ehrlich introduced the notion of stereoselectivity into biomedical science in his side-chain theory of immunity (Gilbert & Greenberg 1984). He based his theory partly on what was known concerning the chemistry of asymmetric molecules, claiming that the destruction of bacterial toxins by antibodies depends on an intimate chemical relationship. Further studies on spatial features lead to a hypothesis proposed in 1933 which accounted for differences between physiological actions of stereoisomers (Eas- son & Stedman 1933). That hypothesis claimed that an effective interaction between an asymmetric compound and its receptor macromolecule involves at least three points of attachment (fig. 1). It provided a scientific rationale for most instances of stereoselectivity known at that time. Since then, many lines of evidence have supported the general notion that spatial features play a key role in interactions between a variety of biologically active molecules, such as enzymes and substrates or antibodies and antigens (Gil- bert & Greenberg 1984). It is also noteworthy that many fundamental biological molecules such as deoxyribose (I) in DNA, ribose (11) in RNA, and most animo acids (e.g. (L)- alanine (111)) in proteins are stereoisomers, which suggests

that stereoselective processes were involved in the origin of life (Abernethy 1972).

Nomenclature in brie$ It is important for anyone interested in stereoselective processes to understand the terms used for describing spatial features in molecules. This section presents some of the most common terms and provides sufficient information for dealing with the examples mentioned in this review. Further information on stereochemical nomenclature is available elsewhere (IUPAC 1970; Gutsche & Pasto 1975; Smith & Lehmann 1984).

Stereoisomers are compounds that have the same molecular formula and the same functional groups bonded in the same fashion, but which differ in the three-dimensional arrangement of the atoms or groups. Thus, stereoisomers contain identical kinds and number of atoms and bonds, but they differ in the way the atoms and bonds are oriented in space.

A well-known example of stereoisomers concerns the two forms of an amino acid such as alanine (I11 and IV). The site of asymmetry in alanine arises due to the fact that there are four different atoms bonded to the C2 carbon atom. Those bonds can be envisioned as projecting towards the four corners of a pyramid (i.e. a tetrahedon) in which the

6 I

B I

/ ,---._

Fig. 1. Schematic diagram for the three-point attachment hypothesis. The areas marked abs, cbs and dbs indicate binding sites for groups, A, C and D, respectively. Note that only the molecule represented on the left has the proper spatial arrangement for good fit to the three-point binding site.

322 DONALD F. SMITH

C2 carbon atom is at the center (fig. 2). When four different atoms are bonded to carbon in that way, there are two possible arrangements and the molecules are asymmetric because they cannot be superimposed on their mirror image. Nowadays, mirror-image stereoisomers are usually called enantiomers, and the term chiral (from the Greek word for “hand”), rather than asymmetric, is usually preferred. Another important term is configuration (sometimes called absolute configuration) which refers to the actual arrangement of atoms in space as determined by chemical bonds.

The chemist Emil Fischer was the first to propose a means of denoting the configuration of enantiomers. He knew, about 100 years ago, that the direction to which an enantiomer diverted plane polarized light (i.e. either to the right (dextrorotatory) or to the left (levorotatory)) was influenced by factors such as sample concentration, temperature, light wavelength, solvent and pH of aqueous solution, so that the sign of rotation was useless as an indicator of molecular configuration. Therefore, he invented a means of denoting the absolute configuration (i.e. the actual three-dimensional arrangement of atoms about a chiral center) in a molecule. First, he chose the enantiomers of glyceraldehyde as stan- dards and arbitrarily assigned the symbol (D) to the dextrorotatory (i.e. (+))form and the symbol (L) to the levorotatory (i.e. (-)) form (V). Then, he generalized the procedure to several types of organic compounds and invented a two- dimensional system, now known as Fischer projection, for representing spatial features in such compounds (VI). Brief- ly, a Fischer projection is drawn by orienting the main chain of a molecule vertically with the C-1 at the top. The groups that are shown bonded horizontally to the chiral atom project toward the viewer whereas the vertical groups project away from the viewer. The symbols (D) and (L) are used for designating the location of the adjacent group of highest priority on the horizontal axes at the chiral site (left-hand side corresponds to (L)-configuration and right-hand side corresponds to (D)-COnfigUratiOn).

In retrospect, Fischer’s choice of symbols appears to have been a poor one, because his (D,L)-nomenclature is often

confused with the (+,-)-system, which is also sometimes denoted by the symbols (d) and ( I ) . It is, therefore, important to note that Fischer’s nomenclature based on the symbols (D)- and (L)- is independent of the (+, -)-nomenclature. For example, the sign of optical rotation of (L)-glyceraldehyde (V) is (-) whereas the sign of rotation of (L)-alanine (111) is (+).

Fischer’s (D,L)-notation turned out to be cumbersome for denoting the configuration in certain enantiomers, and a new and better system has been devised by Cahn, Ingold and Prelog. It uses the symbols ( R ) (from Latin, rectus “right”) and (S) (from Latin, sinister, “left”) to denote configuration at chiral sites (fig. 3). The (R,S)-system of nomenclature is also independent of the (+, -)-system. Fur- thermore, although both the (R,S)- and the (D,L)-systems denote the absolute configuration at chiral sites in molecules such as enantiomers, several combinations of symbols can arise (fig. 4).

Another topic that requires attention is relations between biological activity and prefix used for designating absolute configuration in closely related compounds such as con- geners. Although one might expect there always to be a direct relation between the stereochemical prefix and biological active in a series of enantiomeric pairs, that expec- tation is sometimes wrong due to differences in the priority of atoms bonded at a chiral center. For example, the most toxic enantiomer of fonofos is the @)-form (VII), whereas the most toxic enantiomer of its congener, fonofos oxon, is the (5‘)-form (VIII) (Ariens et al. 1988). It is, therefore, usually wise to examine the actual spatial orientation of atoms in molecules, rather than to rely solely on stereochemical nomenclature as a basis for concluding whether there are consistent relations between absolute configuration and biological activity in sets of enantiomers.

Enantiomers are not the only type of stereoisomers. An- other type is called diastereomers. Diastereomers are stereoisomers that, in addition to having the same structural formula and containing the same number of identical atoms

Fig. 2. Three-dimensional diagram for the tetrahedral nature of carbon bonding. Carbon (C) is shown at the center of a tetrahedron with its four possible bonds projecting towards the corners of the tetrahedron. Two of the bonds are represented by solid lines which denote bond axes in the plane of the page, whereas short parallel lines are used to denote a bond axis projecting behind the plane of the page (i.e. away from the viewer) and a filled triangle is used to indicate a bond axis projecting up from the plane of the page (i.e. towards the viewer).

Fig. 3. Nomenclature for a chiral center. Assignment of the prefixes (R) and (S) for denoting the absolute configuration at a chiral center is determined by the Cahn-Ingold-Prelog Sequence Rules. The main principle in these rules is to rank the atoms directly attached to the chiral center in order of decreasing atomic number. The group with the highest atomic number is ranked first; the group with the lowest atomic number is ranked fourth. In the figure, the ranking of atoms is A > B > C > D. The lowest ranking atom or group is represented in the figure by a dotted line which indicates that it is oriented away from the viewer, i.e. below the plane of the paper, whereas the other three groups are to be envisioned as projecting toward the viewer. The analogy of an automobile steering wheel with tree radial bars is a useful one to visualize. The prefix (R) is assigned to a clockwise sequence of priorities for A, B, and C, while (3 is used to denote a counterclockwise sequence.

MiniReview

OH I

H o w C H 2 N H 2

HO ‘ (R)-(L)-( -)-Noradrenaline

N H 2 I

H 0 2 C 4 C H 2 S H H

(R)-(L)-( +)-Cysteine

( R)-(D)-( - )- Alanine

(R)-(D)-( + )-Tryptophane

STEREOSELECTIVITY OF DRUG ACTION 323

OH

(S)-(D)-( + )-Noradrenaline

HSH2C x 3 C 0 2 H H

(S)-(D)-( - )-Cysteine

NH2

H02.A H C H 2

(S)-(L)-( +) -Alanine

NH2

H O 2 . A H C H 2 8

/ \ -

(9-(~)-( -)-Tryptophane

Fig. 4. Examples of the (R,S)-, (D,L)- and (+,-)-systems of nomenclature showing enantiomers with all possible combinations of symbols. Note the independence between the symbols given by each of the three systems!

and bonds, have more than one chiral center. For example, the stereoisomers of tartaric acid are diastereomers (IX, X and XI). There are two mirror-image forms of tartaric acid that are optically active ((2S,3S)-( -)- and (2R,3R)-( +)-) and one form, called meso-(2R,3S)-tartaric acid (from Greek, mesos, “middle”), that shows no optical activity because it has a plane of symmetry.

Diastereoisomerism can also arise due to the arrangement of atoms bonded to double bonds or rings. The general term for such stereoisomers is geometrical isomer. The prefixes ( E ) (from German, entgegen, “opposite”) and (Z) (from German, zusammen, “together”) are used to denote the spatial arrangement of atoms around a double bond (e.g. (a- and (E)-Zbutendioic acid (XI1 and XIII, respectively)), whereas the prefixes cis (from Latin, “on this side”) and trans (from Latin, “across”) are used to describe geometrical isomers that arise due to the arrangement of atoms bonded to rings. In many cases, the terms cis and trans refer to compounds with two chiral centers, so that (R,S)-nomenclature is required to describe fully the configuration of the molecule (e.g. (lR,2R)-cis, (1S,2S)-cis-, (1S,2R)-trans- and (1 R,2S)-trans-2-phenylcyclopropylamine (XIV, XV, XVI and XVII, respectively).

Another common stereochemical term is conformation,

which refers to the momentary spatial arrangement of atoms not directly bonded to each other in a molecule. Most biologically active molecules such as drugs and ligands are flexible and have, therefore, an infinite number of confor- mations.

Terms such as chair and boat (XVIII and XIX, respectively) are used for describing conformational features in ring structures. Terms such as synclinal and antiperiplanar are used for denoting spatial relations between groups that are free to rotate about a carbon-carbon bond axis, and Newman projections are often used for showing such conformational features (XX and XXI).

Stereoselective drug action. Stereoselectivity is a fundamental property of life processes and spatial features are, therefore, involved in therapeutic actions and side effects of many drugs (Smith 1989b; Ariens et al. 1983; Drayer 1986; Testa & Jenner 1978). Many drugs are, nonetheless, marketed as stereoisomeric mixtures, i.e. they are composed of two or more stereoisomers and, as a rule, little is known about therapeutic actions and side effects of each of the compounds in such mixtures. Moreover, much research has failed to take the stereochemistry of drugs and their metabolites into account, resulting in countless reports containing “pseudoscientific nonsense” (Ariens 1984). The possibility that the therapeutic effect of a drug may reside in one stereoisomer while adverse effects may reside in another emphasizes the importance of knowing the effects of each compound in stereoisomeric mixtures. Luckily, much current attention is being given in pharmacology and toxicology to the role of spatial features in effects of drugs. In addition, sensitive and reliable methods are becoming available for synthesizing individual stereoisomers and for measuring their concentrations in biological material. These developments are expected to have far- reaching consequences in the medical sciences within coming years. In the following, a brief account is given on some of the findings concerning the role of stereoselectivity in drug action in the hope of stimulating further interest in this topic.

Cell division and teratogens. Mechanisms governing cell division and growth reside in chromosomes, which are asymmetric molecules. Genetic information is transcribed from chromosomes by RNA which is also asymmetric. RNA mediates the synthesis of proteins which are composed mainly of asymmetric amino acids. Clearly, cellular division and growth is highly dependent on stereoselective processes.

One hazard of drugs is that they may cause chromosomal damage, resulting in birth defects. Perhaps the most well documented example of drug-induced teratogenicity concerns the sedative thalidomide. That drug was marketed as a racemic mixture, but it was withdrawn from the market due to severe birth defects in thousands of children born to women who had taken the racemate during pregnancy (Lenz 1966). Later, the teratogenic effects of thalidomide were

324 DONALD F. SMITH MiniReview

shown to reside mainly in the (S)-enantiomer (XXII) (Bla- schke et al. 1979). If only the (R)-enantiomer had been used, then the thalidomide tragedy might have been avoided.

Cancer and antineoplastic drugs. Several approaches have been used for taking advantage of stereoselectivity in the battle against cancer. One approach has been to try to make compounds that are toxic for cancer cells but not for normal cells. Since many cellular processes are stereoselective, it might be possible to invent drugs which have the proper stereoselective requirements for poisoning only cancer cells. This approach has been applied in the development of carrier molecules for introducing toxins into cancer cells (Angerer et al. 1989). One successful project involved the use of the (L)-enantiomer of phenylalanine as carrier molecule in melphalan (XXIII), in which antitumour activity was obtained against carcinosarcomas and mela- noma.

Another approach has been to study antitumour activity of stereoisomers which interact selectively with certain metabolic processes. It is important to recognize that enzymes are composed of amino acids, which are themselves stereoisomers. As a result, most metabolic processes show some degree of stereoselectivity due to spatial features in enzymes (Testa & Jenner 1978). Drugs that are tailor-made to inhibit a particular enzyme stereoselectively are called “antimeta- bolites” (Angerer et al. 1989). Such compounds have been used as antineoplastic agents. One such drug is the (D)- enantiomer of cytosine arabinoside (XXIV), which interfers with ribonucleoside metabolism. It showed antitumour activity in a variety of tests and is used for treating leukemia. On the other hand, the (L)-enantiomer of cytosine arabinoside is devoid of activity against leukemia.

Stereoisomers have also been used for studying other mechanisms of antineoplastic action. For example, the (2)- and (&)-isomers of diamminedichloroplatinum (cisplatin (XXV) and transplatin (XXVI), respectively) have been shown to differ in terms of their antitumour activity, with cisplatin being the most potent (Angerer et al. 1989). Note that the terms cis and trans are used here to describe the spatial relations of substituents bonded to platinum in a planar fashion. The rate of hydrolysis of transplatin was greater than that of cisplatin, so less of the former molecule was available for intracellular effects. In addition, cisplatin was more potent than transplantin as inhibitor of DNA synthesis and cell growth, and as enhancer of the formation of DNA intrastrand cross-links. These and other findings indicated that the formation of DNA intrastrand cross- links was probably the major mechanism involved in the antitumour activity of these compounds.

Allergy, immunity and antiallergic drugs. Although most of the details of Ehrlich’s theory on immunity, proposed in 1897 to account for interactions between antibodies and toxins, proved to be incorrect, his work alerted medical scientists to the potential importance of spatial features in health and disease (Gilbert & Greenberg

1984). Today, the importance of stereoselective processes in events that trigger cellular and humoral immune reactions is well-established (Mouton et al. 1985).

Most of the symptoms of allergy are caused by the liber- ation of vasoactive substances, such as histamine and serotonin, by cells containing large amounts of antibodies formed towards antigens (Hermecz & Sipos 1989). Various antihistaminic drugs are used for treating allergies, and some of them interact stereoselectively with physiological processes involved in the allergic response. The enantiomers of chlorpheniramine (XXVII) have, for example, been found to differ by a factor of 200 as antihistaminic agents (Casy 1989a). On the other hand, only small differences were observed between antihistaminic properties of the enantiomers of promethazine (XXVIII) (Hermecz & Sipos 1989). Evidently, spatial features in mechanisms involved in histamine release are more sensitive to differences in the enantiomers of chlorpheniramine than to those of promethazine. Further evidence for the importance of spatial features in the effects of antihistaminic agents comes from studies on clemastine (Casy 1989a). This drug has two chiral centers, so 4 stereoisomers are possible. The marketed drug has the (2R,aR)-configuration (XXIX) and is the most potent stereoisomer of the four in tests of histamine antagonism.

Many P-adrenoceptor agonists, used in the management of allergic reactions such as asthma, also show stereoselectivity in their interactions with mechanisms involved in bronchodilation (Hermecz & Sipos 1989). The enantiomers of clenbuterol (XXX) differ markedly, for example, in their potency on tracheal muscles, with the (+)-form being 100-1000 times stronger than its antipode (Waldeck & Wid- mark 1985). Similarly, marked differences were observed between the effects of the enantiomers of trimetoquinol (XXXI) on bronchodilation mediated by P-adrenoceptors (Kiyomoto et al. 1978).

Bacterial infections and antibiotics. Therapeutic actions of many drugs used for treating bacterial infections depend on stereoselective processes (Mitsch- er et al. 1989). This is the case because infectious bacteria depend on DNA for their existence, and drugs used for treating such infections often require a specific chirality in order to be effective. Some stereoisomeric antibiotics have been developed specifically for forming a complex with bacterial DNA and a subunit of DNA gyrase, an essential bacterial enzyme. Two examples of such drugs are methylflumequine (XXXII) and ofloxacin (XXXIII), in which the (S)-forms are much more potent than their antipodes against microorganisms (Gerster et al. 1987; Hayakawa et al. 1985).

The antituberculosis agent ethambutol is another drug in which spatial features play a crucial role in pharmacological activity. The (+)-diastereomer (XXXIV) is more than 200 times more active than the (-)-form against tuberculosis (Wilkinson et al. 1961). Furthermore, penicillin and related antibiotics depend for their activity on interactions with chiral processes in target bacterial cells (Mitscher et al.

MiniReview STEREOSELECTIVITY OF DRUG ACTION 325

1989). For example, penicillin V (XXXV) has the (3S,SR,6R)-configuration and is far more active than stereoisomers with other configurations as antibiotic, presumably due to the goodness-of-fit toward the vital bacterial enzyme p-lactamase.

Cardiovascular system and stereoisomeric drugs. The cardiovascular system has a variety of stereoselective mechanisms. Many of them are probably due to the fact that the (R)-enantiomers of adrenaline and noradrenaline (XXVI) are endogenous compounds which act as agonists at adrenergic receptors in the heart and vasculature. Many cardiovascular mechanisms are stereoselective toward those compound as well as others with similar spatial features (Patil et al. 1975).

Antiarrhythmics. P-Adrenoceptor antagonists are among the most popular drugs used for the treatment of cardiac ar- rhythmias. They owe their antiarrhythmic effects mainly to a reduction in activity in the sympathetic nervous system. Antiarrhythmic actions of P-adrenoreceptor antagonists depend in part on their spatial features (Fowler 1989). Thus, (S)-propranolol (XXXVII) is far more potent than its antipode in preventing experimentally-induced fibrillation caused by isoprenaline and a mineralocorticoid in rats (Green et al. 1983). The metabolism of P-adrenoceptor antagonists is also stereoselective (Ariens 1984). Numerous studies have shown, for example, that the enantiomers of propranolol, as well as those of structurally-related drugs, often differ in terms of their bioavailability and pharmacological effects in humans, due in part to stereoselective metabolism (Fowler 1989). Many pharmacokinetic studies have, however, neglected that fact (Ariens 1984). It is noteworthy that most analytical methods for measuring the concentrations of drugs in biological samples provide information on only the total amount of compound present after adminstration of a racemic drug, without distinguishing between enantiomers. Consequently, the results obtained in many studies on stereoisomers have failed to indicate the pharmacokinetics and pharmacodynamics of each compound in stereoisomeric mixtures.

Blockade of calcium channels is also a stereoselective process which is involved in the action of certain antiarrhythmic drugs (Triggle & Swamy 1983). Verapamil is a calcium channel blocker, and its antiarrhythmic activity resides primarily in the (9-enantiomer (XXXVIII), although differences in the effects of the enantiomers are typically relatively small (Fowler 1989). Much current interest on antiarrhythmics is aimed at making drugs with en- hanced stereoselectivity for interactions at mechanisms governing the entry of calcium into cells. One interesting compound is a dihydropyridine derivative called PN 202-791 (Hof et al. 1985). Its enantiomers differ markedly in their effects on calcium entry into vascular smooth muscle; the (R)-enantiomer inhibits calcium entry whereas the (5')-form (XXXIX) enhances it. These remarkable findings emphasize that, in addition to quantitative differences, qualitative dif-

ferences can also occur between pharmacological effects of enantiomer s .

Blood pressure and antihypertensives. Hypertension is one of the most widespread health problems in industrialized countries. The physiological systems which contribute to hypertension typically show some degree of stereoselectivity (Abou-Gharbia et al. 1989). The stereoselectivity of P-adrenoceptors and of calcium channels, which are involved in antihypertensive actions of many drugs, were mentioned in the preceding section. Since the renin-angiotensin system is also involved in the development of hypertension, drugs which influence that system have been of interest as antihypertensive agents. The strategy involved in the development of such drugs has focused mainly on preventing enzymatic conversion of angiotension I to the potent endogenous vasoconstrictive agent angiotensin 11. The angiotensin converting enzyme (ACE), like most other enzymatic processes, has unique spatial features that make it stereoselective. Some of the stereoselective requirements of ACE were worked out by Cushman and co-workers (Cushman et al. 1978; Ondetti et al. 1977). On the basis of differences between ACE and carboxypeptidase A, they postulated that the hypothetical active site of ACE involved three-points of attachment consisting of a cationic carbonyl-binding site, a zinc atom and a hydrogen binding site. They reasoned on the basis of their model that a succinyl amino acid should provide a potent and specific inhibitor of ACE. Their work led to the discovery of captopril (XL) and enalapril (XLI), which are effective in the treatment of hypertension (Croog et al. 1986; Davies et al. 1984).

Blood clotting and anticoagulants. Blood clotting is dependent upon specific proteins (Biggs & Rizza 1984). Blood clotting prevents excessive bleeding on injury, and is also implicated in thromboembolic diseases. An important step in the coagulation process involves the enzyme-dependent synthesis of prothrombin, and a number of anticoagulant drugs owe their actions mainly to inhibition of that step. In particular, coumarins are competitive inhibitors of that process, and a number of them show stereoselectivity, both in their therapeutic actions and in their metabolism (O'Reil- ly & Trager 1989). For example, the (9-enantiomer of warfarin is several times more potent than its antipode as anticoagulant. In addition, there are differences in the metabolism of the enantiomers of warfarin; 7-hydroxylation is the most favoured metabolic pathway for (9-warfarin (XLII), whereas the favoured pathway for (R)-warfarin is 6-hydroxylation. The anticoagulant actions of the enantiomers of phenprocoumon also differ, with the (,!?)-form (XLIII) being the more potent of the pair (Jahnchen et al. 1976).

Inflammation and anti-inflammatory drugs. Inflammation is a biological process governed by a variety of hormonal agents such as prostaglandins (Trang 1980). Most prostaglandins are stereoisomers, formed from arach- idonic acid by the enzyme cyclooxygenase. The anti-inflam-


matory activity of many drugs involves inhibition of that enzyme (Stecher 1989). Two such compounds are the racemic anti-inflammatory agents ibuprofen and fenoprofen. Studies carried out in vitro have shown that their (q-enan- tioners (XLIV and XLV) are far more potent than their antipodes as cyclooxygenase inhibitors. However, no marked difference between anti-inflammatory actions of the (R)- and (3-enantiomers has been observed in vivo, because the less active (@-form is converted to the (3-form by stereoselective enzymatic processes (Adams et al. 1976; Ru- bin et al. 1985). The rate and degree of conversion of the less active enantiomer of these anti-inflammatory drugs to the more active one depends on a variety of factors, such as liver and kidney function and stereoselective protein binding (Rendic et al. 1980).

Pain and analgesics. Pain is a complex sensation involving a variety of neuro- transmitters. From a clinical standpoint, the major neuronal mechanism of interest involves opiates and opioid peptides (Watkins & Mayer 1982; Hahn & Pasternak 1984). Most opiates and opioid peptides are stereoisomers that produce their analgesic effects by interacting with stereoselective receptors (Bhargava 1984; Hahn & Pasternak 1984).

Morphine is a prototype of opiate pain-killers. It has 5 chiral centers and its analgesic potency resides in the (5R,65',9R,l35',14R)-( -)- enantiomer (XLVI). A variety of stereoisomers, structurally-related to morphine have been examined for analgesic actions (Casy 1989b; Bhargava 1984). Levorphanol (XLVII) is a potent analgesic which binds stereoselectively to opiate receptors, while its antipode lacks such effects. The enantiomers of pentazocine, a benzo- morphan derivative, also differ markedly in terms of their analgesic properties. The ( -)-enantiomer (XLVIII) is the most potent form. Pentazocine is, nevertheless, marketed as the racemate. Another racemic analgesic drug of interest from a clinical standpoint is methadone, which is used for maintenance therapy of opiate addicts. The opiate-like properties of @)-methadone (XLIX) are much greater than those of the (3-form (Casy 1989b). Further work on the stereoselectivity of neuronal processes involved in opioid mechanisms may lead to new potent and nonaddictive analgesic agents as well as antinarcotic drugs.

Psychic disorders and psychotropic drugs. Disturbances in neurotransmission appear to play a role in most psychic disorders. Schizophrenia is, for example, thought to reflect abnormalities in dopaminergic processes (Carlsson 1988) whereas depression is considered to reflect malfunctions in noradrenergic and/or serotonergic mechanisms (Siever 1987; Meltzer & Lowy 1987). Numerous studies have been carried out in recent years using stereoisomers to investigate molecular mechanisms involved in neurotransmission.

Some remarkable findings have been obtained with the enantiomers of the dopamine analogue 3-PPP (343-h~- droxypheny1)-N-n-propylpiperidine) (Hjorth et al. 1983).

Both enantiomers were agonists at dopaminergic autorecep- tors, but they had opposite effects at postsynaptic receptors; the (8-form (L) acted as an agonist while its antipode was an antagonist. Dopaminergic receptors also show stereoselectivity towards antipsychotic drugs. For instance, the (3- isomer of flupentixol (LI) is a therapeutically effective antipsychotic agent which inhibits dopaminergic neurotransmission, while the (@-isomer lacks those effects (Hyttel et al. 1984; Johnstone et al. 1978). Sulpiride is also used for treating psychosis, and its enantiomers differ in their actions on dopaminergic transmission. (R)-sulpiride (LII) is much more potent than its antipode as antagonist of dopaminergic receptors while the acute toxicity of (R)-sulpiride is less than that of the (3-form in animal studies (Hyttel et al. 1984; Smith 1989b). It would be interesting to know whether (R)- and (8-sulpiride differ in their effects on mental disorders.

Stereoisomers have also been used to study possible mechanisms of action of antidepressant drugs. Most antidepressant drugs inhibit the neuronal reuptake of noradrenaline and/or serotonin @berg-Wistedt 1982), and the stereoisomers of antidepressant drugs have often been found to differ in potency as reuptake inhibitors (Smith 1986 & 1989b). The enantiomers of nomifensine differ, for example, with respect to their potency as inhibitors of synaptosomal uptake of noradrenaline and serotonin, with activity resid- ing mainly in the (8-(+)-form (LIII) (Schacht & Leven 1984). The relative potencies of the enantiomers of another antidepressant drug, tranylcypromine, differ at noradrenergic and serotonergic uptake sites. The (15',2R)-( +)- enantiomer (XVI) is more potent than its antipode as inhibitor of serotonin uptake, whereas their potency is reversed toward noradrenaline uptake (Tuomisto & Smith 1986). Two clinical trials have been carried out comparing effects of the enantiomers of tranylcypromine as antidepressants. One study showed that the (-)-enantiomer was slightly better than its antipode (Escobar et al. 1974), while opposite results were obtained in the other study (Moises & Beckmann 198 1). Clearly, further clinical trials with individual stereoisomers of racemic antidepressant drugs are needed in order to determine whether spatial features are related to their therapeutic actions and/or side effects.

Gabaminergic receptors have been implicated in actions of drugs used mainly for treating epilepsy, sleep disturbances and anxiety. The stereoselectivity of gabaminergic processes is well documented (Krogsgaard-Larsen et al. 1984). In one study (Olsen et al. 1981), cis and trans-aminocyclopentane- 1-carboxylate) (LIV) were used for studying the binding properties of gabaminergic receptors. High- and low-affinity receptors were distinguished on the basis of the binding properties of those and other stereoisomers. In another study (Ticku et al. 1985), the enantiomers of l-methyl- 5-phenyl-5-propylbarbituric acid (MPPB) showed opposite effects on the gabaminergic receptor complex; the (R)-( -)- enantiomer (LV) counteracted seizures induced by its antipode, and their binding properties differed. These findings suggest that also neuronal mechanisms involved in convul- sive disorders are stereoselective.

MiniRevie w STEREOSELECTIVITY OF DRUG ACTION 327

General discussion. This MiniReview has presented an account on the role of spatial features in drug action in various branches of therapeutics. Life scientists are clearly in the midst of dem- onstrating the importance of spatial features in biological and pharmacological processes. Stereoselectivity is a general rule of Nature (Rauws 1983), so it is likely that stereoselective processes contribute in one way or another to either the causes or the cures of most human disorders. Thus, studies on stereoselectivity can be expected to provide further information on molecular mechanisms responsible for health and disease. It is, therefore, of interest to speculate briefly on possible implications of stereoisomers and stereoselective processes for pharmacology and toxicology.

One implication concerns the use of stereoisomeric mixtures, such as racemates, as therapeutic agents. The biomedical sciences are far behind the chemical sciences in their awareness as to the importance of asymmetry in life processes. Most textbooks on pharmacology and toxicology have failed to deal with stereoselective processes, despite the fact that about 25% of the drugs on the market are stereoisomeric mixtures (Ariens et ul. 1988). Since the individual components in a stereoisomeric drug mixture often have different actions, it is always of interest to know the pharmacokinetics and pharmacodynamics of each compo- nent. Such information can lead to the removal of compounds in stereoisomeric drug mixtures that contribute to side effects and toxicity, the so-called “isomeric ballast” (Ariens et al. 1988). In addition, it can improve our understanding of relations between molecular structure and pharmacological activity and will, hopefully, lead to improve- ments in therapeutic agents.

Another implication of work on stereoisomeric drugs and stereoselective processes concerns the policies used by scientific journals for judging whether reports are suitable for publication. Lack of knowledge and/or lack of interest in stereochemical issues in the past has resulted in the publication of countless studies in which the stereochemical composition of drugs has been ignored and pseudoscientific nonsense has been published (Ariens 1984). Much of the blame for this situation can be given to the journals, since they have failed to provide contributors with strong de- mands and adequate instructions for dealing properly with stereoisomeric drugs. There is an easy remedy (Ariens 1989). The editorial boards of scientific journals can require that contributors always indicate the stereochemical composition of drugs. In the case of racemates, the prefix ruc- should be used (e.g. rac-propranolol), whereas the appropriate prefix (e.g. (E/Z)- or cisltrans-) should be used for mixtures of geometrical isomers.

A third implication of work on stereoselective processes in pharmacology and toxicology concerns the methods used in such studies. It has been difficult in the past to obtain pure stereoisomers, because of problems in their synthesis. In addition, methods have been lacking for measuring individual stereoisomers in biological material. Fortunately, ad-

vances have been made in recent years in methods for both stereospecific drug synthesis and stereoselective drug analysis (Wainer & Drayer 1988). Those methods can provide purer drugs as well as new strategies for research on molecular mechanisms governing stereoselective processes. The information obtained may be of particular use in developing more effective ways of preventing and curing diseases that depend in part on stereoselective processes, such as allergy, cancer, AIDS and some mental disorders.

A fourth implication concerns relations between biomedical sciences. Advances in our understanding of stereoselective processes can be expected to go hand-in-hand with advances in computer sciences and bioengineering. The topography of receptors may be mapped by 3- or 4-dimensional computer graphics, and biotechnology may enable pure stereoisomers to be tailor-made for potent and effective interactions with receptor sites. New biomedical measurements, based on stereoselectivity, may be used for characterizing diseases as well as for determining the proper treatment. The availability of numerous sets of pure stereoisomers may also provide valuable tools for research on spatial features in biological systems, and can be expected to lead to even more potent therapeutic agents devoid of adverse side effects.

A fifth implication of work on stereoselective processes concerns the possibility of altering spatial features in abnormal macromolecular processes, such as those involved in genetic disorders. It may be possible to repair genes in the human chromosome using drugs that interact stereoselectively with DNA. Abnormal nucleic acid sequences in chromosomes as well as abnormal amino acid sequences in enzymes and other proteins might be changed to normal ones by stereoselective interactions. Success in such work will certainly require extensive research on stereoselectivity in cellular processes, but once that information is available, it may be possible to design drugs with proper spatial features for obtaining the desired effects. Such an approach might be particularly useful against cancer as well as health problems caused by ageing.

A sixth implication concerns reducing pollution. Many industrial and agricultural products consist of stereoisomeric mixtures which contribute to pollution on a world-wide scale. One way of reducing pollution would be to use as little as possible of only the biologically most active and/or most biodegradable isomer, for example, of pesticides and herbicides (Ariens 1987; Ariens et al. 1988). In some cases, the least active isomer can be either recycled and converted chemically to the active form or used in other ways. Thus, attention to stereoselective processes and to the use of stereoisomers can be both more economical and safer for the environment.

328

I I1 I11 IV V VI VII VIII IX X XI XI1 XI11 XIV xv XVI XVIl XVIII XIX XX

XXI

XXII XXIII XXIV XXV XXVI XXVII XXVIII XXIV xxx XXXI XXXII XXXIII XXXIV XXXV XXXVI

DONALD F. SMITH

Index to compounds Deoxyribose Ribose (L)-( +)-Manine (D)-( -)-Manine (L)-( -)-Glyceraldehyde Fischer projection of (L)-( -)-glyceraldehyde (R)-Fonofos (9-Fonofos oxon (2S,3S)-( -)-Tartaric acid (2R,3R)-( +)-Tartaric acid (2R,3S)-meso-Tartaric acid (Z)-ZButendioic acid (.!?)-2-Butendioic acid (1 R,2R)-cis-2-Phenylcyclopropylamine (1 S,2S)-cis-2-Phenylcyclopropylamine (1 S,2R)-trans-2-Phenylcyclopropylamine (1 R,2S)-trm-2-Phenylcyclopropylamine Cyclohexane in chair conformation Cyclohexane in boar conformation 2-Phenylethylamine in synclinal conformation (Newman projection) 2-Phenylethylamine in anriperiplunar conformation (Newman projection) (8-Thalidomide Melphalan 1 -P-(D)-arabinofuranosykytosine Cisplatin Transplatin rac-Chlorpheniramine rac-Promethazine (2R,aR)-Clemastine ruc-Clenbuterol rac-Trimetoquinol (a-Methylflumequine Ofloxacin

Penicillin V (RM - )-Noradrenaline

(3S,8S)-( +)-EthambUtol

XXXVII ij-(- j-Propranolol XXXVIII (S)-( -)-Verapamil XXXIX (S)-( +)-202-791 (isopropyl4-(2,1,3-benzoxadiazol-4-yl)-

1,4-dihydro-2,6-dimethyl-5-nitro-3-pyridin~arboxylate) XL Captopril XLI Enalapril XLII ($)-Warfarin XLIII (a-Phenprocoumon XLIV @)-Ibuprofen XLV (S)-Fenoprofen XLVI (5R,6S,9R,13S,14R)-( -)-Morphine XLVII Levorphanol XLVIII (-)-Pentazocine XLIX (R)-( -)-Methadone L (S)-( - )-PPP (3-(3-hydroxyphenyl)-N-n-propyl-

LI (2)-Flupentixol LII (R)-Sulpiride LIII (S)-Nomifensine LIV trms-3-Aminocyclopentane-1-carboxylate LV (R)-( -)-MPPB (l-methyl-5-phenyl-5-propylbarbituric

piperidine)

acid)

MiniReview

MiniReview STEREOSELECTIVITY OF DRUG ACTION 329

INDEX TO STRUCTURAL DRAWINGS

NH2 NH2

H~C&COOH HOOC$CH~

1 1 1 IV 1 I 1

xxx I x XL 5 XL I

V VI v11 VIII

XLIV

IX X XI XI I XI I I HO OH

XLV XLV I XLVI I

xv I XVI I

XLVI I I XLIX

& W XVI I I XIX

n

H

NHZ

xx xx I

L LI L I I

XXI I

J55 Ho-cw on

XXIV

XXI I I

XXX xxx I XXXI 1

XXXI I I XMlV xxxv

xxxv I xxxv I I xxxv I I 1


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